The invention generally relates to diagnostic imaging of tumors and specifically relates to diagnostic imaging of tumors using phospholipid analogs.
The early detection of cancer has been one of the primary goals of modern imaging technology, since the identification of a suspected tumor in a localized stage significantly improves the chances for successful treatment and elimination of the cancerous tissue. A large number of imaging strategies have therefore been designed, using a variety of techniques and modalities, to aid the physician in making an accurate diagnosis as early as possible.
Unfortunately, conventional imaging techniques such as computerized tomography (CT) and MRI (magnetic resonance imaging) are limited in their ability to afford a conclusive diagnosis of a suspected lesion, since they are only capable of observing differences in the density or morphology of tissues. A more invasive and costly biopsy procedure is often necessary to provide a definitive diagnosis. In contrast, nuclear medicine techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) can provide functional or biochemical information about a particular organ or area of interest. However, the success of these nuclear imaging techniques depends in large part on the selective uptake and detection of appropriate radiopharmaceuticals. Selective uptake, in turn, depends upon the development of radiopharmaceuticals with a high degree of specificity for the target tissue. Unfortunately, the tumor-localizing agents developed thus far for oncological applications have had only limited application.
For example, one of these prior art compounds, 67Ga gallium citrate, was originally identified for its ability to accumulate in tumor tissue. Unfortunately, 67Ga gallium citrate is taken up by a variety of other non-cancerous lesions as well, including inflammatory lesions, and unacceptable amounts of radioactivity can also accumulate in liver and spleen tissue. The rapid buildup of a radiopharmaceutical in these organs can seriously interfere with the imaging of nearby lesions and also negatively impacts the dosage that can safely be given to a patient.
An alternative approach has been to develop radiolabeled monoclonal antibodies (Mabs) directed to tumor-specific antigens. However, these monoclonal antibodies are specific only to the particular tumor tissue for which they have been produced, and therefore will not localize generally in neoplastic tissue. Moreover, the use of Mabs for diagnostic imaging has lead to additional problems, including varying degrees of antigen expression, low tumor uptake, non-specific binding and adverse immunogenic reactions.
In an attempt to address these problems, the present inventors have recently identified and developed a series of novel compounds demonstrating useful tumor specificity. See, e.g., U.S. Pat. Nos. 4,925,649; 4,965,391; 5,087,721; 5,347,030 and 6,417,384; all of which are herein incorporated by reference. It is believed that these radioiodinated phospholipid ether analogs take advantage of a unique biochemical characteristic of malignant tumor cells; i.e. the large concentration of naturally-occurring ether lipids in the tumor cell membranes relative to corresponding normal tissues. Although the precise mechanism of action is not fully understood, the prevailing hypothesis is that the phospholipid ether analogs become entrapped in tumor membranes. Accordingly, these compounds localize in tumor tissue and remain in place for diagnostic and/or therapeutic applications.
The selective retention of the radiolabeled phospholipid ether analogs described in the above patents has been demonstrated in a variety of rodent and animal tumor xenografts and not in spontaneous tumor models which are thought to more closely mimic the human disease. Unfortunately, the data obtained from these studies has also demonstrated a relatively rapid clearance of the radiopharmaceutical compound from the blood, and an undesirable accumulation by non-target tissues. As noted above, non-target tissue uptake can decrease the efficacy of radiodiagnostic imaging by creating high background activity, or by causing excessive exposure of radiosensitive tissues to the injected radioactivity.
Accordingly, there remains a significant need in the art for radiopharmaceuticals which exhibit a rapid clearance from non-target tissues as well as an extended half-life in the plasma, while still retaining its specificity and avidity for neoplastic tissue. Such an agent should not only assist in the non-invasive imaging of primary tumors and metastases, but should also serve as a carrier for a cytotoxic agent for site-specific eradication of malignant tumor tissue, especially as it relates to most frequently diagnosed forms of cancers. It is further desirable that radiopharmaceuticals are selective for malignant tumors and not precancerous tissues including adenomas and hyperplasia.
Approximately 147,000 new cases of colorectal cancer are diagnosed each year in the United States. Thus colorectal cancer is the fourth most common cancer, accounting for 60,000 deaths per year.1 Treatment depends primarily on the cancer stage, but may include surgery, radiation, chemotherapy, and/or radiofrequency or cryo ablation. In routine follow-ups for colorectal cancer patients, however, determination of carcinoembryonic antigen (CEA), a colorectal tumor marker, and repeat colonoscopies5 fail to detect recurrent disease in over 50% of patients.6 Therefore, there is a need for development of additional methods for detection of recurrent disease. Further, during treatment and diagnosis using CT scanning and RF ablation, functional information from CT scans is difficult to obtain. With contrast-enhanced helical CT, the tumor vascularity may be assessed to some degree, but there is no way of accurately determining if viable tumor cells remain within the RF lesion. In addition, the thermal lesions created by RF normally have a rim of inflammation surrounding them on post procedure CT scans for up to 6 months post-procedure. PET scanning has been used to follow post-ablation patients, but the rim of inflammation surrounding RF thermal lesions normally displays increased uptake, even in the absence of viable tumor. This decreases the sensitivity and specificity for early detection of recurrent tumor. Accordingly, agents like NM404 that are selective for and retained indefinitely by malignant tumor cells are preferable, unlike FDG which is not selective for tumor cells and goes to infectious sites and hyperplasias (Barret's Esophagus). Moreover, compounds like NM404 containing 124I, which has a 4 day physical half-life and can be shipped anywhere in the world, are preferable as compared to FDG which has a 110 minute half-life and therefore may only be have limited distribution within 200 miles of the production site. Further compounds like NM404 that undergo prolonged retention (not metabolized) are preferable since it is more likely that they may have significant therapeutic potential when mated with an appropriate radioisotope like 131I. Also, compounds like NM404, which can be labeled with a variety of iodine isotopes and have expanded versatility (diagnosis and therapy as well as a tool for experimental animal studies) are preferable as compared to FDG, which is limited to 18F for PET scanning or potentially 19F (stable) for magnetic resonance imaging albeit at very low sensitivity levels. Regardless of its tumor targeting ability, FDG due to its rapid metabolism in tumor cells, does not have potential for therapy. Therefore, other compounds are needed to investigate post RF local recurrences. Likewise, if the tumor becomes metastatic, either by progression or recurrence of the local tumor, a hybrid imaging modality (PET and CT combination), replacing post-procedure separate CT and PET scanning is highly desirable.
Moreover, even where chemotherapy is the mode of treatment, improved monitoring of the response to chemotherapy is essential. Therefore, development of an early marker to study response to chemotherapy to allow physicians to quickly discontinue use of ineffective chemotherapeutic regimens without exposing patients to the toxicity of prolonged treatments is desirable. Where External Beam Radiation Therapy is an alternate treatment for patients with tumors of similar histology, tumors may have dramatically different responses to curative-intent external radiation therapy (XRT). Some patients with rectal cancer treated with pre-operative radiation will have a complete response, while others with similar histology (at the light microscopy level) will have a poor response to treatment and disease will recur. Response to radiation is a predictive factor for ultimate tumor control and survival for many cancers, including many gastrointestinal cancers, lung cancer, head and neck cancer, and gynecologic cancers. Most response characterization methods, while very predictive of response, are performed after completion of treatment. While some intra-treatment clinical assessments are useful in adjusting treatment,14 in most cases there is no accurate method of predicting tumor response during actual treatment. Such a test, especially one applicable to a broad range of tumor sites and histologies, would obviously be very useful and desirable. Other treatment and diagnostic methods include molecular assays that have been proposed to predict response to therapy, and recent efforts include use of DNA microarrays to identify genetic changes that correlate with response or lack of response to treatment. These are investigational and none are in routine clinical use.
Yet other methods of diagnosis and treatment include use of imaging modalities to predict response during XRT treatment. Intra-treatment PET scans using FDG are under active investigation, wherein the isotope uptake in the primary tumor midway through radiation therapy is compared to the pre-treatment uptake. Several retrospective studies suggest patients with continued strong uptake during treatment have poorer tumor control outcomes than patients whose tumors are less FDG-avid during treatment.15 However, more effect screening, diagnostic and treatment methods for various cancers are extremely desirable.
Other well observed tumors include malignant gliomas that are the most common type of primary brain tumors. Despite aggressive treatment with surgery, radiation, and chemotherapy, most patients harboring these tumors have less than a two-year survival after diagnosis. Recent advances in neuroradiology and magnetic resonance imaging (MRI) have made a significant impact in early diagnosis and treatment of these tumors. Most malignant gliomas, however, have an infiltrative component, which is poorly differentiated from edematous brain tissue by present imaging techniques. It is often this component of the tumor that is most difficult to treat and responsible for local recurrence. Undoubtedly, better visualization of invasive glioma cells is desirable for significant therapeutic treatment.
Likewise, pancreatic cancer is a highly lethal disease with the poorest likelihood of survival among all of the major malignancies. It is the fifth leading cause of cancer death in the United States and of all the newly diagnosed cancers in the United States, 2% per year are due to pancreatic cancer. However, it is one of the most highly lethal diseases which accounts for 5% of all cancer deaths. Miller B A, et al. NIH Pub. No. 96-4104. Bethesda, Md. 1996. This is demonstrated by the fact that there are no five-year survivors in patients with unresectable disease. In addition, although surgical resection offers the only hope for cure, the five-year survival after resection is only 20%. Geer R J, Brennan M F. Am J Surg 1993; 165:68-72; Yeo C J, Cameron J L, et al., Ann Surg 1997. Although PET scanning with 18-FDG has shown promise in imaging a variety of other primary cancers, it appears to have only limited ability to improve upon the imaging capability of CT scan for patients with pancreatic cancer, particularly in assessing for metastatic disease. Kasperk R K, Riesener K P, et al., World J Surg 2001; 25:1134-1139; Sendler A, Avril N, et al., World J Surg 2000; 24:1121-1129. Thus, there remains a need for a method of accurately imaging patients with occult metastatic pancreatic cancer.
Hepatocellular cancer is the most common solid organ malignancy worldwide, due to its common etiology of chronic liver damage from hepatitis or alcoholism. Incidence rates vary markedly, from 2.1 per 100,000 in North America to 80 per 100,000 in high-incidence regions of China. The risk of developing HCC in patients with cirrhosis is 1-6% per year. Although resection is the only curative option, only 10-30% of patients are candidates for surgery at the time of presentation, due to either poor hepatic reserve or the presence of unresectable or metastatic disease. Attesting to the aggressive nature of this disease, the five-year survival is only 15-35% after curative resection. Treiber G. Digestive Diseases (2001) 19:311-323.
Breast cancer is a major health concern for women in the United States today. It was anticipated that nearly 216,000 women in the US alone would be diagnosed with breast cancer in 2004 and of these 40,000 were expected to die. Accurate assessment of local, regional and distant metastatic spread is critical for optimal disease treatment and management. The development of a non-invasive imaging modality that would allow detection and or characterization of local or distant breast cancer metastases including lymph node involvement would represent a significant advancement in the management of this disease. Although mammography is the current screening method of choice for initial detection of breast cancer, histologic confirmation and regional spread to neighboring lymph nodes are typically evaluated via biopsy. More sophisticated imaging methods including scintigraphic scanning with 99mTc-Sestamibi and 18F-FDG PET scanning have now been extensively examined, but have not impacted treatment planning significantly due mainly to unpredictable specificity. Wahl R L. Quart J of Nucl Med (1998) 42:1-7. The role of PET scanning has indicated efficacy, however, in monitoring tumor response to chemotherapy. Smith I C, Welch A E, et al., J of Clin Oncol (2000) 18:1676-1688; Schelling M, Avril N, et al., J of Clin Oncol (2000) 18:1689-1695. Radiation therapy has a well-established role in the treatment of breast cancer due mainly to the sensitivity of many solid epithelial tumors, including infiltrating ductal carcinoma, to ionizing radiation. DeVita V, Hellman S, Rosenberg S. Cancer: Principles and Practice of Oncology, 6th edition. Philadelphia (PA): Lippincott, Williams and Wilkins, 2002, pp. 1667-1680. The most common indication for radiation in breast cancer is as adjuvant treatment following lumpectomy or mastectomy. In this context, radiation therapy has been shown to dramatically decrease the incidence of local and regional recurrence by sterilizing microscopic deposits in these tissues. Chemotherapy is offered when the patient has metastatic disease or is deemed to have an increased risk for occult metastases. In this latter indication, that of adjuvant chemotherapy administration, studies confirm improved survival in patients receiving adjuvant chemotherapy or hormonal therapy. Radiation is also used in the palliative setting with good effect in reducing the pain and volume effects of metastases in solid organs and bone. Many patients relapse after definitive therapy for reasons that are multifactorial. Acquired resistance to radiation and chemotherapy undoubtedly contributes to recurrence after primary therapy. Additionally, the use of radiation is associated with specific toxicities which are generally late-occurring and dose-limiting. Fibrosis, nerve damage, and soft tissue necrosis can be severe if excessive doses of radiation are used. Arm lymphedema is the most common and dreaded toxicity for breast cancer patients, and results most commonly from the combination of axillary dissection (done for diagnostic purposes) and adjuvant radiation to the axilla.
In contrast to new anticancer drugs that are largely targeted to receptors or molecules specific to each particular tumor type, new compounds that rely on a common mechanism applicable to a variety of different tumor types are extremely desirable.
Hence, there remains a dire clinical need for noninvasive breast cancer imaging techniques that afford both high sensitivity and specificity. Moreover, the potential to deliver a therapeutic dose of iodine-131 simultaneously to both primary and metastatic tumors is a significant added benefit.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States today. Surgical resection in appropriately selected patients offers the best chance for long-term survival and may be curative. Accurate pre-operative assessment of local, regional and distant metastatic spread is thus critical for optimal management. Evaluation of the mediastinal lymph node status is essential because nodal metastasis, which occurs in nearly half of all patients with NSCLC, is probably the most frequent barrier to cure. Accurate staging may also spare patients the morbidity of unnecessary, non-curative surgical procedures.
Imaging with FDG-PET scanning is quickly becoming the gold standard for imaging NSCLC, due to improved sensitivity rates, particularly when compared with CT imaging. However, this is an expensive imaging test which is not available in most community practices. Hence, there remains a need for an imaging technique which is sensitive, specific, and uses resources which are readily available to most patients.
Positron-emission tomography (PET) scanning with 18F-FDG has generated considerable interest as an imaging technique. A recent study prospectively compared the ability of a standard approach to staging for NSCLC (CT, ultrasound, bone scanning, etc) and PET scanning to detect metastases in mediastinal lymph nodes and distant sites. Pieterman R M, vanPutten J W G, Meuzzelaar J J, Mooyaart E L, Valburg W, Koeter G H, Fidler V, Prium J, Groen H J M. Preoperative Staging of Non-Small Cell Lung cancer with Positron-Emission Tomography. New Eng J Med 343:254-261, 2000. Mediastinal involvement was confirmed histopathologically, and distant metastases were confirmed by other imaging tests. The sensitivity and specificity of PET for detecting mediastinal metastases were 91% and 86%, respectively; for detecting distant metastases, 82% and 93%, respectively. This compares to sensitivity and specificity for CT scanning of mediastinal involvement 75% and 66%, respectively. Another study compared imaging with FDG-PET, CT, and histology results. Overall sensitivity, specificity, and accuracy of PET for staging mediastinal nodes (n=168 in 54 patients) was 96%, 93% and 94%, as compared to 68%, 65%, and 6% with CT. Gupta N C, Graeber G M, Bishop H A. Comparative efficacy of positron emission tomography with fluorodeoxyglucose in evaluate of small (<1 cm), intermediate (1 to 3 cm), and large (>3 cm) lymph node lesions. Chest 117(3):773-778, 2000. Limitations of PET scanning, however, include the cost, limited availability, inability to detect lesions under 1 cm, and lack of specificity, particularly in patients with inflammatory or granulomatous disease. Stokkel M P, Bakker P F, Heine R, Schlosser N J, Lammers J W, Van Rijk P P. Staging of lymph nodes with FDG dual headed PET in patients with non-small cell lung cancer. Nucl Med Communications 20(11):1001-1007, 1999; Kapuco L O, Meltzer C C, Townsend D W, Keenan R J, Luketich J D. Fluorine-18-fluoro-deoxyglucose uptake in pneumonia. J Nucl Med 39(7):1267-1269, 1998.
Conventional anatomic imaging techniques such as CT scanning are also not good at predicting survival following treatment despite tumor shrinkage following therapy. In a recent study involving 56 NSCLC patients receiving treatment with concurrent cisplatin-based chemo/radiotherapy or radiotherapy alone for advanced disease, response by conventional CT imaging did not correlate with survival. MacManus M P, Hicks R J, Wada M, Hoff A, Matthews J, Wirth A, Rischin D, Ball D L. Early F-18 FDC-PET response to radical chemoradiotherapy correlates strongly with survival in unresectable non-small cell lung cancer. Proc ASCO 19:483a, 2000. Response by FDG-PET scans, however, did correlate strongly with survival (p=0.0006). Survival from the date of a follow-up PET scan was 84% and 84% at 1 and 2 years respectively for 24 patients who had achieved a complete response on PET, but only 43% and 31% of the 32 patients who did not (p=0.010). These results corroborate similar findings reported recently by other authors. Patz E F Jr, Connolly J, Herndon J. Prognostic value of thoracic FDG PET imaging after treatment for non-small cell lung cancer. Am J Roentgenology 174(3):769-774, 2000; Vansteenkiste J F, Stroobants S G, Dupont P J, DeLeyn P R, Verbeken E K, Deneffe G J, Mortelmans L A, Demedts M G. Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose positron emission tomography scan in non-small cell lung cancer: An analysis of 125 cases. JClin Oncol 17(10):3201-3206, 1999; Ahuja V, Coleman R E, Herndon J, Patz E F Jr. The prognostic significance of fluorodexoyglucose positron emission tomography imaging for patients with non-small cell lung carcinoma. Cancer 83(5):918-924, 1998.
Therefore, a readily available radiopharmaceutical that could accurately identify and potentially treat early metastatic disease in the patients with NSCLC would have an important impact on patient care, in terms of both staging and response to therapy. Although PET imaging procedures are gaining effectiveness in this area, the cost and inaccessibility severely limits its practical application. There remains a need for an accurate functional imaging technique based upon a tumor-specific function that can non-invasively screen the whole body using relatively inexpensive and widely available imaging devices.